PDF(Pubmed)
Abstract：
Tumor immunotherapies targeting PD-(L)1 exhibit anti-tumor efficacy in only 10-30% of patients with various cancers. Literature has demonstrated that a \"hot tumor\" which contains high T lymphocytes in the tumor microenvironment exhibits a better response to immunotherapies than a \"cold tumor.\" This study aimed to investigate whether tumor-intrinsic IFNα and CXCL10 determine the recruitment and activation of CD8+ T cells to become \"hot tumor.\" In this study, we found that CXCL10 overexpressed in a variety of tumors including lung, colon, and liver tumors with a correlation with PD-L1. High PD-L1 and CXCL10 are associated with better survival rates in tumor patients receiving immunotherapies. IFNs-downstream transcriptional factor IRF-1 and STAT1 were correlated with PD-L1 and CXCL10 expression. We demonstrated that IRF-1 and STAT1 were both bound with the promoters of PD-L1 and CXCL10, sharing the same signaling pathway and determining IFNs-mediated PD-L1 and CXCL10 expression. In addition, IFNα significantly increased activation marker IFNγ in PBMCs, promoting M1 type monocyte differentiation, CD4+ T, and CD8+ T cell activation. Particularly, we found that CD8+ T lymphocytes abundantly expressed CXCR3, a receptor of CXCL10, by flow cytometry, indicating that tumor-intrinsic CXCL10 potentially recruited CD8+ T in tumor microenvironment. To demonstrate the hypothesis, immunotherapy-sensitive CT26 and immunotherapy-resistant LL/2 were used and we found that CT26 cells exhibited higher IFNα, IFNγ, CXCL10, and PD-L1 levels compared to LL/2, leading to higher IFNγ expression in mouse splenocytes. Moreover, we found that CD8+ T cells were recruited by CXCL10 in vitro, whereas SCH546738, an inhibitor of CXCR3, inhibited T cell migration and splenocytes-mediated anti-tumor effect. We then confirmed that CT26-derived tumor was sensitive to αPD-L1 immunotherapy and LL/2-tumor was resistant, whereas αPD-L1 significantly increased T lymphocyte activation marker CD107a in CT26-derived BALB/c mice. In conclusion, this study revealed that CXCL10 expression is correlated with PD-L1 in tumors, sharing the same signaling pathway and associating with better immunotherapeutic efficacy. Further evidence in the syngeneic tumor models demonstrated that immunotherapy-sensitive CT26 intrinsically exhibited higher IFNα and CXCL10 compared to immunotherapy-resistant LL/2 to recruit and activate CD8+ T cells in the tumor microenvironment, exhibiting \"hot tumor\" characteristic of sensitizing αPD-L1 immunotherapies.
摘要：
靶向PD-(L)1的肿瘤免疫疗法仅在10-30%的患有各种癌症的患者中表现出抗肿瘤功效。文献表明，在肿瘤微环境中含有高T淋巴细胞的“热肿瘤”比“冷肿瘤”对免疫疗法表现出更好的反应。“这项研究旨在调查肿瘤固有的IFNα和CXCL10是否决定CD8+T细胞的募集和激活，从而成为热门肿瘤。“在这项研究中，我们发现CXCL10在包括肺癌在内的多种肿瘤中过度表达,结肠,和肝脏肿瘤与PD-L1相关。在接受免疫疗法的肿瘤患者中，高PD-L1和CXCL10与更好的生存率相关。IFN下游转录因子IRF-1和STAT1与PD-L1和CXCL10表达相关。我们证明IRF-1和STAT1均与PD-L1和CXCL10的启动子结合，共享相同的信号通路并决定IFN介导的PD-L1和CXCL10表达。此外,IFNα显着增加PBMC中的激活标记IFNγ，促进M1型单核细胞分化，CD4+T,和CD8+T细胞活化。特别是,我们发现CD8+T淋巴细胞大量表达CXCR3，CXCL10的受体，通过流式细胞术，表明肿瘤固有CXCL10可能在肿瘤微环境中募集CD8+T。为了证明这个假设，使用免疫疗法敏感性CT26和免疫疗法抗性LL/2，我们发现CT26细胞表现出更高的IFNα，IFNγ,与LL/2相比，CXCL10和PD-L1水平导致小鼠脾细胞中更高的IFNγ表达。此外，我们发现CD8+T细胞在体外被CXCL10募集，而CXCR3抑制剂SCH546738抑制T细胞迁移和脾细胞介导的抗肿瘤作用.我们随后证实CT26来源的肿瘤对αPD-L1免疫疗法敏感，而LL/2-肿瘤耐药，而αPD-L1在CT26来源的BALB/c小鼠中显著增加T淋巴细胞活化标志物CD107a。总之,这项研究表明，CXCL10的表达与肿瘤中的PD-L1相关，共享相同的信号通路，并与更好的免疫治疗功效相关联。同系肿瘤模型中的进一步证据表明，与免疫疗法抗性LL/2相比，免疫疗法敏感性CT26内在地表现出更高的IFNα和CXCL10，以招募和激活肿瘤微环境中的CD8T细胞。具有致敏αPD-L1免疫疗法的“热瘤”特征。
